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PERCORTEN®- V (desoxycorticosterone pivalate)
Injectable Suspension
The Standard In Canine Hypoadrenocorticism Therapy
Canine Hypoadrenocorticism:
Diagnosis and Treatment of an Emerging Disease
Canine Addison’s Disease (hypoadrenocorticism) has always been
extremely difficult to diagnose. Its symptoms are so often confused with those
of other conditions that it is known as “The Great Pretender.” Because Canine
Addison’s Disease is so under-diagnosed, it is believed to have a low prevalence. However, with more careful screening, it may emerge as a more common ailment than previously believed.
We at Novartis Animal Health US, Inc. understand the importance of properly
diagnosing this serious and potentially fatal disease, and have created this technical monograph to serve as your definitive guide to canine hypoadrenocorticism.
With this monograph, we are proud to educate you about PERCORTEN®-V
(desoxycorticosterone pivalate), the only FDA-approved* product to treat
Addison’s Disease in dogs. If you have any questions, please contact your
Novartis Animal Health US, Inc. Representative, or Novartis Animal Health US,
Inc. Professional Services at 1-800-637-0281.
* NADA # 141-029, Approved by FDA.
Table of Contents
1
2
Introduction ...................................................................................3
1.1 History of Addison’s Disease ..........................................................3
1.2 Clinical significance of hypoadrenocorticism ...................................3
Anatomy and pathophysiology................................................5
2.1 Adrenal glands in health and disease ...............................................5
2.2 The role of mineralocorticoids ..............................................................6
2.3 The role of glucocorticoids ...................................................................6
3
4
5
6
7
8
9
Diagnosis .................................................................................................7
3.1 Predisposing factors ..............................................................................7
3.2 Clinical signs .........................................................................................8
3.3 Laboratory tests .....................................................................................9
PERCORTEN®-V (desoxycorticosterone pivalate)............................11
4.1 Product description..............................................................................11
4.2 Pharmacology ......................................................................................11
4.3 Clinical review ....................................................................................12
4.4 Dosing and safety................................................................................13
4.5 Addisonian crisis dosing .....................................................................14
4.6 Product benefits ..................................................................................15
Monitoring and maintenance .................................................16
Frequently asked questions.....................................................17
Client information sheet ..........................................................19
References ....................................................................................22
PERCORTEN-V product insert....................................Back Cover
1. Introduction
The first human cases of hypoadrenocorticism were described in the mid-1800s
by an English physician, Thomas Addison, hence the name “Addison’s Disease.”1
The clinical syndrome included anemia, lethargy, poor heart function and gastrointestinal upset.1 It wasn’t until after the 1930s that glucocorticoids and mineralocorticoids, then finally commercially available, were used to treat and save
humans from this otherwise fatal disease.1
1.1 History of Addison’s Disease
The first canine case of hypoadrenocorticism was reported in 1953.1 At
that time, there were two compounds available for the treatment of
Addison’s Disease, DOCA and DOCP; however, neither was approved for
use in dogs. By 1960, a new oral drug for treating hypoadrenocorticism
was introduced, Florinef ®* (fludrocortisone acetate), but again approved
for human use only. In 1989, Novartis Animal Health US, Inc. (then Ciba-Geigy)
provided DOCP to veterinarians for use as an “investigational drug” to treat dogs
with Addison’s Disease.
Hypoadrenocorticism is characterized by inadequate production of glucocorticoids (cortisol) and/or mineralocorticoids (aldosterone) by the adrenal cortex.1-3
Primary hypoadrenocorticism, or Addison’s Disease, results from the destruction
of the adrenal cortices and is fatal when untreated.1-3 Secondary hypoadrenocorticism occurs when the bilateral adrenal cortex atrophies due to insufficient
secretion of adrenocorticotrophic hormone (ACTH) from the pituitary gland
and is associated with only glucocorticoid deficiency.1-3
1.2 Clinical significance of hypoadrenocorticism
Hypoadrenocorticism is a serious and potentially life-threatening endocrine
disorder.2 The actual incidence of canine adrenocortical insufficiency at one
large veterinary hospital has been calculated at 0.36 dogs per 1000. It has been
suggested that these small numbers represent under-diagnosis (rather than
minimal occurrence) of the disease. On average,2 in a typical practice with two
veterinarians, each of whom sees approximately 1,500 dogs per year, should
expect to diagnose one case of adrenal insufficiency each year.
3
It has been demonstrated that PERCORTEN-V is well tolerated with a low
incidence of side effects. In a small percentage of treated dogs, depression,
excessive thirst and urination, digestive, skin and coat changes, weakness, and
injection site reactions (pain, abscesses) may occur. Some of these effects may
resolve with adjustments in dose or interval of PERCORTEN-V or concomitant
glucocorticoid administration. Do not use in pregnant dogs or in dogs that are
suffering from congestive heart disease, severe renal disease, or edema. For
additional information, please see product insert on back cover.
* Florinef is a registered trademark of Bristol-Myers Squibb.
Because many of the clinical signs of Addison’s Disease resemble those of other
illnesses, it has been referred to as “The Great Pretender,” 3 and can be
an especially frustrating and challenging situation for the companion animal
practitioner.1,2 Some dogs with Addison’s Disease may appear healthy and active,
which can lead to misdiagnosis of the disease. The often obscure
presenting signs and the subtle physical abnormalities induced by hypoadrenocorticism complicate an already difficult diagnosis. However, careful observation and a thorough medical history, in conjunction with specific laboratory tests,
can reveal an accurate diagnosis. In cases where “classic Addisonian signs” are
observed — hyperkalemia, hyponatremia, bradycardia and decreased blood pressure — hypoadrenocorticism should be strongly suspected.2
There are many common causes of primary hypoadrenocorticism which include
a variety of etiologies. In cases where lymphocyte and plasma cell infiltration is
identified in the adrenal cortex, an immune-mediated basis has been
suggested.1,3 Other less common causes include: infections (coccidioidomycosis,
blastomycosis, or tuberculosis), hemorrhagic infarctions, granulomatous disease,
metastatic neoplasia, trauma, and amyloidosis.1,3 Primary hypoadrenocorticism is
seen most often in young to middle-aged dogs, an interesting contrast to the
many other canine endocrinopathies, which tend to affect middle-aged to older
dogs.1,3 Even though any gender can be affected, females seem to be predisposed.
Secondary hypoadrenocorticism in small animals is usually due to excessive or
prolonged administration of exogenous glucocorticoids.2 In these cases,
normal adrenal function usually returns within a few months after gradual withdrawal of medication.2
PERCORTEN®-V (desoxycorticosterone pivalate), approved
by the FDA in 1998, is the only veterinary product
approved for treating canine hypoadrenocorticism. It has a
well-established safety and efficacy profile.
1998 marks the year of
the first FDA-approved
veterinary drug for the
treatment of canine
hypoadrenocorticism —
PERCORTEN-V from
Novartis Animal Health
US, Inc.
• Causes of primary hypoadrenocorticism include a variety of etiologies.
• Primary hypoadrenocorticism (Addison’s Disease) is fatal if untreated.
• Addison’s Disease in dogs is complex and can be difficult to diagnose
Summary – Section 1
•
•
as the signs often mimic those of other diseases.
Hypoadrenocorticism is often under-diagnosed.
PERCORTEN-V is the only FDA-approved product for the treatment
of canine hypoadrenocorticism.
4
2. Anatomy and
pathophysiology
The importance of the adrenal glands is easily recognized by the number
of vital substances that they secrete. Many of these hormones are required for
normal physiologic function, as well as during times of stress (e.g., cortisol,
epinephrine, norepinephrine, estrogen, testosterone, cortisone, aldosterone).
2.1 Adrenal glands in health and disease
The adrenal gland is a two-part structure located on the cranial pole
of each kidney. The inner portion, the medulla, secretes the catecholamines
adrenaline and epinephrine. The outer portion, the cortex, consists of three
distinct functional zones, each with a particular secretory purpose:1
• The outer zona glomerulosa of the cortex is primarily involved with the
synthesis and secretion of the mineralocorticoid, aldosterone.
• The middle zona fasciculata synthesizes and secretes glucocorticoids, of which
cortisol is the most important in mammals.
• The inner zona reticularis of the adrenal cortex primarily secretes
adrenal sex steroids (androgens and estrogens).
Gross anatomy of
Figure 1.
the normal kidney
with adrenal glands
5
Adrenal cortical functioning is often maintained even in the face of severe compromise.1 It is estimated that the significant operational reserves of
mammalian adrenal glands allow for up to 90% impairment before clinical signs
appear.1 Approximately 10% of animals with hypoadrenocorticism exhibit signs
only after stressful situations (e.g., disease, trauma, surgery, travel, kenneling).1
However, as glandular reserves decline over time, an adrenal crisis (Addisonian
crisis) may occur without an obvious precipitating event.1 This is a life-threatening medical emergency requiring immediate and intensive treatment. (See
Section 3.2 Clinical signs and Section 4.5 Addisonian crisis dosing.)
In up to 5% of dogs, other endocrine diseases (i.e., hypothyroidism, diabetes
mellitus, hypoparathyroidism) accompany or co-exist with Addison’s Disease. 4
All mineralocorticoids control electrolyte regulation and fluid balance.1
However, aldosterone, the primary adrenal mineralocorticoid, is important in
Addison’s Disease because of its specific effect on sodium, chloride, and
water resorption.1 Aldosterone also promotes potassium excretion, leading to
extracellular fluid volume expansion and increased blood pressure.1
2.2 The role of mineralocorticoids
Transverse-section
Figure 2.
of the adrenal gland
In mineralocorticoid deficiency, potassium excretion is diminished, causing
excessive sodium loss and hyperkalemia.1,4 Hyponatremia, in turn, leads to
decreased circulating blood volume, resulting in prerenal azotemia, hypotension,
dehydration, weakness and depression.1,4 Hyperkalemia may also lead to myocardial toxicity.1,4
Glucocorticoids, the most important of which is cortisol, affect nearly all somatic
tissues.1 Glucocorticoids are important regulators of glucose, protein, and fat
metabolism; they also inhibit inflammation.1 Glucocorticoids are released in
times of stress and are controlled by the hypothalamus (corticotropin-releasing
hormone (CRH)) and the pituitary gland (ACTH).1
2.3 The role of glucocorticoids
Glucocorticoid deficiency often manifests as anorexia, vomiting, melena, lethargy,
and weight loss; it also predisposes to hypoglycemia, and results in impaired
excretion of water free of sodium.4
• An Addisonian crisis is a life-threatening medical emergency requiring
Summary – Section 2
immediate and intensive treatment.
• Severely damaged adrenal glands can continue to function.
• Aldosterone is the most important mineralocorticoid.
• Cortisol is the most important glucocorticoid.
• Glucocorticoid deficiency often manifests as anorexia, vomiting,
melena, lethargy and weight loss.
6
3. Diagnosis
In 1996, a retrospective medical records review of 225 dogs diagnosed with
hypoadrenocorticism was conducted to evaluate the clinical and laboratory findings over a 14-year period.5 In this study, no specific risk factors for Addison’s
Disease could be identified; however, results showed correlation with age and
breed, and a predisposition in females5 (approximately 70% to 85% of hypoadrenal dogs are female1).
3.1 Predisposing factors
Those breeds at a higher risk of developing Addison’s Disease are listed in
Table 1. On the contrary, the breeds less likely to develop the disease are the
Lhasa Apso and Yorkshire Terrier.5
Table 1. Breeds of dogs at greater risk of developing Addison’s Disease2-5
•
•
•
•
•
•
Great Dane
Portuguese Water Dog
Rottweiler
Standard Poodle
West Highland White Terrier
Wheaten Terrier
Relative to age, research studies show a somewhat higher incidence of Addison’s
Disease in the 4- to 7-year age group (average age at diagnosis has been reported as
4.3 to 5.4 years).3 Then, as dogs age beyond 7 to 10 years, the odds of
developing Addison’s Disease begin to decline. For dogs over 10 years old,
the odds ratio approaches the level of the 1- to 4-year age group. Dogs younger than
1 year are the least likely to be diagnosed with hypoadrenocorticism. (See Table 2.)
Table 2. Odds of developing hypoadrenocorticism, by age3
7
Age (years)
Odds ratio
0 to 1
0.12
1 to 4
1.01
4 to 7
1.90
7 to 10
1.51
greater than 10
1.06
Hypoadrenocorticism is a chronic disease with a wide range of signs and symptoms. (See Table 3.)
3.2 Clinical signs
Several of the more frequently observed signs, such as lethargy, weakness, and
dehydration, mimic those of many other such common diseases as Renal Failure,
Gastrointestinal Disease, etc.1-4 Additionally, clinical signs are intermittent and
are often described as “waxing and waning.”1-4 Signs may vary between the
chronic case and the acute crisis.4 For example, in some dogs with chronic
hypoadrenocorticism, only a few, mild, intermittent clinical signs may be
observed. In contrast, the dog in acute Addisonian crisis may exhibit signs that
are quite severe and life threatening.4
A thorough medical history is crucial in identifying hypoadrenocorticism.
Sudden episodes of the more common signs, such as vomiting, diarrhea and
weakness, may occur and quickly resolve with fluid and/or glucocorticoid therapy.1,2 However, over time, a repeated pattern of these signs develops which may
suggest progressive adrenal insufficiency.
Table 3. Clinical signs and physical findings of hypoadrenocorticism1-5
Most commonly found: May be present:
•
•
•
•
•
•
Depression/lethargy
Weakness
Dehydration
• Melena
• Hypothermia
Hematemesis
•
• Shaking/tremors
• Polyuria/polydipsia • Painful/sensitive abdomen
Vomiting
Diarrhea
Weight loss
Less often reported:
(PU/PD)
•
•
•
•
•
Anorexia
Bradycardia
Weak pulse
Slow capillary refill
Hair loss
Due to the subtle and intermittent nature of these clinical signs, many dogs with
hypoadrenocorticism are not diagnosed until they are presented in crisis. At this
point, the veterinarian faces a medical emergency with a severely weak dog that
is in hypovolemic shock.1,2
The absence of a discrete set of clinical signs for hypoadrenocorticism contributes
to the complexity of the disease. The nonspecific nature of abnormalities induced
by Addison’s Disease can sometimes mask the actual condition.1 Therefore, in
addition to a thorough medical history and physical examination, the veterinarian
should rely on more advanced methods of diagnosis, including laboratory
screening. (See Section 3.3 Laboratory tests.)
Approximately one-third
of dogs in Addisonian
crisis present with
bradycardia due to
hyperkalemia.2 This is an
important distinguishing
factor in hypoadrenocorticism, as hypovolemia
from other causes is
usually associated with
tachycardia.2 (See Table
4 and Section 4.5
Addisonian crisis dosing.)
8
Table 4. The clinical signs of Addisonian crisis2
• Severe weakness/depression
• Hypovolemic shock
- Pale mucous membranes
- Prolonged capillary refill time
- Weak femoral pulse
- Dehydration
• Bradycardia/arrhythmias
• Acute collapse
Confirmation of primary hypoadrenocorticism is achieved through laboratory analysis, including
a complete blood count (CBC), a serum chemistry profile with an electrolyte panel and a serum
cortisol concentration. Additionally, a urinalysis can be helpful in supporting the diagnosis, as
specific gravity is often less than 1.030 in dogs with adrenal insufficiency.1 (See Table 5.)
3.3 Laboratory tests
Although a CBC is a valuable reference tool, there may be only minimal changes seen in the
hypoadrenal dog.1-3 The lack of a stress leukogram, which one would expect to see in an ill dog,
should raise the suspicion of hypoadrenocorticism.2 Common hematological findings in dogs
with Addison’s Disease include lymphocytosis and eosinophilia.2 Often a normocytic, normochromic, non-regenerative anemia is present, which can be masked by dehydration.1 If
dehydration exists, an increased packed cell volume may be seen.1,2
Classic signs of
Addison’s Disease
include: hyperkalemia,
hyponatremia,
bradycardia, and
decreased blood
pressure.
The chemistry profile also may be unremarkable; however, electrolytes are key indicators of
insufficient adrenal function. Most hypoadrenal dogs have a sodium/potassium ratio of less
than 20:11 (serum sodium is usually <140 milliequivalents per liter (mEq/L), potassium is usually >6.0 mEq/L), although not all hypoadrenal dogs will show these classic electrolyte alterations.1,2 However, electrolyte levels alone cannot differentiate between primary and secondary hypoadrenocorticism.1,2
Frequently, hypoadrenocortcism is misdiagnosed as renal failure due to the similar laboratory
profiles found in both diseases (i.e., hypoatremia, hyperkalemia and hypochloremia).2 Response
to fluid therapy can be used as an indicator; the azotemia associated with Addison’s Disease
often completely resolves with rehydration, while only a partial response is observed in cases
of primary renal failure.2
Table 5. Selected laboratory values in dogs with primary hypoadrenocorticism1
9
FACTOR
NUMBER
NORMAL VALUE
TESTED
NUMBER
MEAN
NUMBER
DECREASED (%)
Serum sodium
Serum potassium
136–50 mEq/L
36
129
3.5–5.0 mEq/L
36
7.2
Sodium/potassium ratio
≥27:1
36
BUN (pre-Rx)
9–25 mg/dl
36
INCREASED (%)
RANGE
22(60)
0(0)
106 –146
0(0)
33(92)
4.7–10.8
19
35(97)
0(0)
11.2–29.1
84
0(0)
33(92)
12–223
BUN (after 24-hr Rx)
9–25 mg/dl
9
25
0(0)
4(44)
11– 47
Serum calcium
8.8 –11.0 mg/dl
13
11.5
0(0)
8(62)
9.3 –14.4
Serum glucose
70–110 mg/dl
24
81.5
8(33)
4(17)
20 –130
Serum bicarbonate
18–24 mM/L
16
14
13(81)
0(0)
9 –19
Urine specific gravity
—
25
1.024
—
—
1.008 –1.062
From Feldman EC: Adrenal gland disease. In Ettinger SJ (ed): Textbook of Veterinary Internal Medicine. 3rd ed. Philadelphia, WB Saunders, 1989, p 1761.
The most accurate and reliable laboratory tool for a definitive diagnosis of hypoadrenocorticism
is the ACTH stimulation test.1-4 This relatively simple assay includes collecting blood samples both
before and after ACTH injections. Serum cortisol levels are compared and a positive diagnosis
may be made when the concentration is undetectable or remains low (<4 micrograms per deciliter
(mg/dl)) after ACTH stimulation. (See Figure 3.)
In cases where electrolyte values are normal, endogenous plasma ACTH concentrations can
distinguish primary from secondary hypoadrenocorticism, but only when the blood sample is
collected before the administration of glucocorticoids.1,2,4 If glucocorticoids are necessary (e.g., in
emergency cases), dexamethasone should be the drug of choice as it does not interfere with the
ACTH stimulation test.2 A high endogenous ACTH level indicates primary disease (i.e., normal
pituitary gland functioning), with the lesion in the adrenal gland.2 Normal values for endogenous
ACTH are between 20 picograms per milliliter (pg/ml) and 100 pg/ml. In dogs with primary
hypoadrenocorticism, levels as high as 554 pg/ml to 4950 pg/ml have been reported.1
Electrolyte levels are also monitored throughout the course of treatment, and are essential for
determining dose adjustments of either PERCORTEN®-V (desoxycorticosterone pivalate)
and/or supplemental steroids. (See Section 5 Monitoring and maintenance.)
The ACTH
stimulation test
1,2
• Plasma cortisol levels are
measured before (baseline) and 2 hours after
(2.2 U/kg IM gel) or
1 hour after (0.25 mg IV)
ACTH administration.
• The normal resting
range for healthy dogs
is 1.0 µg/dl to 5.0 µg/dl;
after stimulation, 6.0
µg/dl to 20.0 µg/dl.
• The pre- and post-ACTH
stimulation levels in
dogs with Addison’s
Disease may be 1.0 µg/dl
or less.
Figure 3. Radioimmunoassay of plasma cortisol concentrations before and after
exogenous ACTH stimulation1
16
Plasma Cortisol (m g/dl)
14
12
10
8
NORMAL
6
4
2
Hypoadrenocorticism
0
Baseline
Plasma Cortisol
TIME
Post Stimulation
Plasma Cortisol
• Certain breeds are more likely to develop Addison’s Disease than other breeds.
• Females are diagnosed more often than males.
• 4- to 7-year age group has the highest incidence.
• “Waxing and waning” clinical signs mimic other diseases.
• A repeated pattern of more common signs (vomiting, diarrhea, weakness) may
Summary – Section 3
suggest progressive adrenal insufficiency.
• One-third of dogs in Addisonian crisis — a medical emergency — present with
bradycardia due to hyperkalemia.
• Electrolytes are key indicators of adrenal insufficiency.
• Response to fluid therapy can be used as an indicator to distinguish between renal
•
•
failure and hypoadrenocorticism.
ACTH stimulation test confirms hypoadrenocorticism.
The lack of a stress leukogram should raise the suspicion of hypoadrenocorticism.
10
4. PERCORTEN -V
®
(desoxycorticosterone pivalate)
PERCORTEN-V is indicated for use as replacement therapy in dogs with
primary adrenocortical insufficiency (Addison’s Disease).
4.1 Product description
It is an injectable aqueous solution containing the pure mineralocorticoid, desoxycorticosterone pivalate (DOCP), a long-acting insoluble ester of desoxycorticosterone acetate (DOCA), and is administered intramuscularly as a microcrystalline depot where the crystals dissolve slowly and are absorbed over time.
Please see Sections 4.3 Clinical review and 4.4 Dosing and safety for clinical
studies demonstrating the safety and efficacy of PERCORTEN-V.
The active ingredient in PERCORTEN-V is desoxycorticosterone pivalate
(DOCP), a mineralocorticoid hormone and an analog of desoxycorticosterone
acetate (DOCA). The mode of action of DOCP is thought to be like that of other
adrenocorticoid hormones; it controls the rate of synthesis of proteins by reacting with the receptor proteins in the cytoplasm to form a steroid-receptor complex. This complex then moves into the nucleus where it binds to chromatin,
which results in genetic transcription of cellular DNA to messenger RNA.
Steroid hormones like PERCORTEN-V appear to induce this genetic transcription and synthesis of specific proteins. DOCP is recognized as having the same
qualitative effects as the natural mineralocorticoid hormone, aldosterone.
4.2 Pharmacology
The structural formula of PERCORTEN-V
11
With proper medical
management — most dogs
suffering from Addison’s
Disease may live a normal
life span.3
The most important therapeutic actions of PERCORTEN®-V (desoxycorticosterone
pivalate) are the effects on sodium absorption and potassium excretion.
PERCORTEN-V increases the rate of sodium absorption by the renal tubules and
the proximal convoluted tubule (although the latter is less important in sodium
retention). It also enhances potassium excretion.
PERCORTEN-V also indirectly increases extracellular fluid volume, which
expands blood volume and improves the venous return to the heart and cardiac
output. This effect prevents the life-threatening hypotensive shock and prerenal
azotemia observed in animals suffering from hypoadrenocorticism.
The results of several well-controlled clinical trials demonstrate the tolerability
and efficacy of PERCORTEN-V.
4.3 Clinical review
The potential toxicity of DOCP was studied using 24 normal dogs. Four groups
of six dogs (three male, three female) were injected with the drug on 3 consecutive days every 28 days for 6 months. The doses given represented an approximate total dose of 3 times, 9 times and 15 times the clinically effective dose (e.g.,
2.2 mg/kg every 25 days). There were no deaths, and transient significant
changes in serum sodium, potassium, and blood urea nitrogen (BUN) levels
resolved by the end of the study. The authors concluded that DOCP was well
tolerated at up to 15 times the clinically effective dose.6
Administration of
PERCORTEN-V prevents
the life-threatening
hypotensive shock and
prerenal azotemia often
observed in dogs with
hypoadrenocorticism.
PERCORTEN-V has been
proven effective in clinical
trials, and is well tolerated
when administered at up
to 15 times the recommended dose.6-7
The efficacy of DOCP in the long-term management of canine hypoadrenocorticism (CHAC) was studied in 46 dogs over 75 days. Thirty-eight of the dogs had
been diagnosed with CHAC and treated with oral fludrocortisone acetate for
1 month to 9 years prior to DOCP therapy. Eight cases were newly diagnosed.
DOCP at 2.2 mg/kg was injected intramuscularly (IM) on days 0, 25, 50 and 75.
Twenty-six dogs also received oral prednisolone once every 24 to 48 hours.
Forty-four of the 46 dogs responded well to DOCP. One dog suffered a crisis of
hypovolemia, hyperkalemia and hypoatremia between days 50 and 75. However,
this dog recovered and eventually responded to DOCP therapy. One dog was
dropped from the study due to poor response to therapy. It was concluded that
DOCP provides adequate control of CHAC via its effect on serum electrolyte
concentrations, and by maintaining tissue perfusion.7
12
Dosing
The initial starting dose of PERCORTEN®-V (desoxycorticosterone pivalate) is
administered as an IM injection at a rate of 2.2 milligrams per kilogram (mg/kg)
of body weight (or 1.0 milligram per pound (mg/lb) of body weight) every 25
days. This dosing schedule may be adjusted depending on response to therapy as
measured by serum sodium and potassium levels (see Section 5 Monitoring and
maintenance). For most dogs, a dose range of 1.65 mg/kg to 2.2 mg/kg (0.75
mg/lb to 1.0 mg/lb) given every 21 to 30 days is effective.
4.4 Dosing and safety
Because PERCORTEN-V is a pure mineralocorticoid, it must be supplemented
with daily oral glucocorticoid hormone replacement (e.g., prednisone or
prednisolone) at a rate of 0.2 mg/kg to 0.4 mg/kg every 24 hours.
As therapy continues, this dosage should gradually be reduced to the lowest
dosage that prevents signs of hypocortisolism (e.g., lethargy, inappetence).
Some dogs with primary adrenal insufficiency ultimately do not require glucocorticoid supplementation, except during times of stress (e.g., disease, trauma,
surgery, travel, kenneling). It has been recommended that all owners have glucocorticoids available to administer to their dogs in times of stress.8
The therapeutic effects of PERCORTEN-V are dependent on functional kidneys.
Animals suffering from hypovolemia, prerenal azotemia and inadequate tissue
perfusion must be rehydrated with intravenous fluid therapy prior to
PERCORTEN-V treatment. Primary renal disease should be ruled out before
starting PERCORTEN-V therapy.
PERCORTEN-V should not be given to pregnant dogs or dogs with congestive
heart failure or edema. (Excessive doses of PERCORTEN-V may cause increased
blood volume and pressure.)
See back cover for the PERCORTEN-V product insert.
Safety
Research has shown that PERCORTEN-V is well tolerated with a low incidence
of serious side effects.
In a study of 822 dogs with Addison’s Disease, the following signs were
observed, and include many of the same clinical signs that appear with canine
hypoadrenocorticism:9
13
• Depression (8%)
• Incontinence (1.7%)
• Polydipsia/polyuria (6%)
• Weight loss (1%)
• Skin and coat changes (5%)
• Diarrhea (1%)
• Anorexia (4%)
• Pain on injection (0.7%)
• Vomiting (4%)
• Injection site abscess (0.01%)
• Weakness (2%)
The initial starting dose of
PERCORTEN-V is 2.2 mg/kg
IM every 25 days.
Most of these side effects resolve with adjustments in PERCORTEN®-V
(desoxycorticosterone pivalate) dose or interval, or glucocorticoid dose.9
Occasionally, dogs on PERCORTEN-V therapy may develop PU/PD, which may
suggest excess glucocorticoids and/or excess PERCORTEN-V. Should this occur,
close monitoring and dose adjustments are required. Initially, the glucocorticoid
dose should be decreased, followed by, if necessary, a decreased PERCORTEN-V
dose at unchanged intervals.
PERCORTEN-V replaces
mineralocorticoid hormones
only. Supplemental
glucocorticoids are essential.
The dog that presents in Addisonian crisis — the end stage of progressively deteriorating adrenal gland disease — is in critical condition with clinical signs signaling a
life-threatening situation.1-4 (See Section 3.2 Clinical signs and Table 4.) This is an
extremely grave state that requires immediate attention and intense treatment.1-4
(See Table 6.)
4.5 Addisonian crisis dosing
In almost all crisis cases, the dog is hypovolemic, hyperkalemic and hyponatremic.1-4
The goal of treatment is to normalize the electrolyte imbalance, correct the hypovolemic shock and re-establish normal homeostasis. This is best accomplished by providing the following:
Addisonian crisis is a true
“life-or-death” emergency.
• Large amounts of intravenous (IV) fluids (i.e., physiologic saline)
• IV glucocorticoids at shock doses (e.g., dexamethasone sodium phosphate
(2.0 mg/kg to 4.0 mg/kg) or dexamethasone (0.5 mg/kg to 2.0 mg/kg))
• PERCORTEN-V at 2.2 mg/kg IM
A lead-II electrocardiogram may be useful in monitoring the response to hyperkalemic therapy.
Once the dog is stable, continue PERCORTEN-V treatment and monitoring.
Table 6. Therapeutic management of an acute adrenal crisis1
1. Collect blood for CBC, chemistry profile, urinalysis, resting cortisol
2. Intravenous 0.9% saline IV (20 – 40 ml/lb) initially
3. ACTH stimulation test
A. 1 U/lb ACTH gel IM -sample at 0 and 2 hours in dogs
B. 0.25 mg synthetic ACTH IM in dogs sample at 0 and 1 hour
4. Glucocorticoid replacement
A. Hydrocortisone hemisuccinate or phosphate, 1– 2 mg/lb IV slowly or
B. Prednisolone sodium succinate, 2 –10 mg/lb IV or
C. Dexamethasone sodium phosphate, 0.25 to 1.0 mg/lb IV5. Add 100 ml of 50% dextrose to
each liter of saline if hypoglycemic
5. Mineralocorticoid replacement
A. Desoxycorticosterone pivalate, 1 mg/lb IM or SQ every 25 days or
B. Fludrocortisone acetate, 0.1 mg/10 lb/day once hydrated and not vomiting or having diarrhea or
C. Hydrocortisone sodium succinate or phosphate as above
6. Sodium bicarbonate-replacement needs calculated as follows: Body weight (kg) x
0.5 x base deficit. Give 1/4 of this amount IV over the first 6 hours of therapy.
Administer only if TCO 2 is <12 mEq/L
7. Monitor:
A. ECG
B. Serum electrolytes
C. BUN, creatinine and urine output
D. Blood glucose, if low initially
14
Because PERCORTEN®-V (desoxycorticosterone pivalate) is a pure mineralocorticoid, it is readily absorbed by the body with a rapid onset of action.
Therapeutic effect is usually observable shortly after the initial IM dose (often
within 24–48 hours).10 To date, thousands of dogs with Canine Addison’s
Disease have been successfully maintained with PERCORTEN-V, and provide
documented proof of product safety as well as efficacy. Easy-to-follow dosing
schedules— one injection every 25 days — plus simple dose adjustments, when
necessary, are important advantages only PERCORTEN-V offers.
4.6 Product benefits
It has been estimated that the average duration of Canine Addison’s Disease is
4.9 years from time of diagnosis.3 However with proper medical management,
hypoadrenal dogs may live a normal life span comparable to the life expectancy
of dogs without adrenal insufficiency.3
PERCORTEN-V, the only FDA-approved veterinary product for Canine
Addison’s Disease, is clearly the drug of choice for treating this serious and
life-threatening condition.
It has been demonstrated that PERCORTEN-V is well tolerated with a low
incidence of side effects. In a small percentage of treated dogs, depression,
excessive thirst and urination, digestive, skin and coat changes, weakness,
and injection site reactions (pain, abscesses) may occur. Some of these effects
may resolve with adjustments in dose or interval of PERCORTEN-V or
concomitant glucocorticoid administration. Do not use in pregnant dogs or
in dogs that are suffering from congestive heart disease, severe renal disease,
or edema. For additional information, please see product insert on back cover.
• PERCORTEN-V is the only FDA-approved veterinary product
indicated for Canine Addison’s Disease.
• PERCORTEN-V is fast-acting, safe and effective.
• PERCORTEN-V is administered once every 25 days.
• PERCORTEN-V is a pure mineralocorticoid and should be
supplemented with daily glucocorticoid hormone replacement.
• The therapeutic effect of PERCORTEN-V is dependent upon functional
kidneys.
• PU/PD in a dog receiving PERCORTEN-V may suggest excessive
glucocorticoids.
• PERCORTEN-V can be used in emergency situations.
• With proper medical management, dogs with Addison’s Disease
may live a normal life span.
Summary – Section 4
15
PERCORTEN-V sets the
standard for treating
today’s canine
hypoadrenocorticism.
5. Monitoring and
maintenance
Because dogs with hypoadrenocorticism require continuous treatment for the rest
of their lives, regular monitoring is necessary to maintain adequate control of the
disease.
Although a safe and efficacious dose of PERCORTEN®-V (desoxycorticosterone
pivalate) has been established, some dogs may require dose adjustments throughout their treatment, a common practice in hormonal therapy. In order to measure
the response to therapy, several repeat serological tests are performed at regular
intervals. These frequent reassessments allow the veterinarian to properly adjust
the dose of PERCORTEN-V, supplemental steroids or both, if necessary, to
effect a positive outcome.
Hormone replacement
therapy is a lifelong
requirement for dogs
with Addison’s Disease.
The most critical laboratory indicators of proper PERCORTEN-V dosing are
electrolyte values. During the initial 2 to 3 months of PERCORTEN-V therapy,
electrolytes should be checked at day 14 and 25. Dosing frequency may be
adjusted based on these results (see Table 7). Once the dog is stabilized, repeat
electrolyte analysis should be completed every 3 to 4 months.
Table 7. Dosing guidelines and frequency adjustments
• If all electrolyte values are normal at day 14 and normal at day 25, change
to 30-day dosing frequency.
• If all electrolyte values are normal at day 14 but abnormal at day 25,
change to 21-day dosing frequency.
• Once stable, check electrolytes every 3 to 4 months.
It is important to note that the most common cause for PERCORTEN-V treatment failure is insufficient supplemental glucocorticoid administration. In times
of stress (e.g., disease, trauma, surgery, travel, kenneling), additional amounts of
supplemental corticosteroids may be required.1-4 Signs of cortisol deficiency
include profound depression, vomiting and diarrhea.
• Routine electrolyte monitoring is an integral part of treatment.
• Stress increases the amount of steroid supplementation needed.
• During the initial two to three months of therapy, electrolytes should be
checked at day 14 and at day 25.
• Some dogs may require dose adjustments throughout treatment.
During stress, dogs need
even more corticosteroid
supplementation.
Summary – Section 5
16
6. Frequently asked
questions
1. Q. What is the vial size and concentration of PERCORTEN®-V
(desoxycorticosterone pivalate)?
A. PERCORTEN-V comes in a 4-ml sterile vial at a concentration of 25.0
mg/ml (a total of 100 mg of active ingredient).
2. Q. What is the appropriate dose of PERCORTEN-V?
A. PERCORTEN-V should be administered by intramuscular (IM) injection
at an initial rate of 2.2 mg/kg (1.0 mg/lb), approximately every 25 days.
(See questions 6 and 7 for additional dosing information.)
3. Q. Does PERCORTEN-V need to be refrigerated?
A. No. PERCORTEN-V may be stored at room temperature between 15° C
and 30° C (59° F and 86° F). It should, however, be protected from light
and freezing. Each unopened vial has a two-year shelf life from the date
of manufacture.
4. Q. Does PERCORTEN-V require reconstitution?
A. No. The PERCORTEN-V vial contains an aqueous suspension at the
given concentration. The vial should be shaken thoroughly before
each use.
5. Q. Can one vial of PERCORTEN-V be used for multiple injections?
A. Yes. Each PERCORTEN-V vial is designed for multiple use. As with any
injectable drug, proper sterile technique should be observed.
17
6. Q. Should PERCORTEN-V be supplemented with a corticosteroid,
such as prednisone or prednisolone? If so, what is the
standard dose?
A. Yes. An oral corticosteroid supplement, such as prednisone or
prednisolone, should be given every day while the dog is receiving
PERCORTEN-V. The usual starting dose for glucocorticoid hormone
replacement is 0.2 mg/kg to 0.4 mg/kg daily. For example, a 30- to 60pound dog would require an initial dose of 5.0 mg/day. During times
of stress, additional amounts of supplemental steroids are required to
maintain adequate control of the disease. (Note: The most common
cause for treatment failure is insufficient supplemental glucocorticoid
administration. Signs of cortisol deficiency include profound depression,
vomiting and diarrhea.)
7. Q. Will corticosteroid supplementation be required indefinitely?
A. As therapy continues, the dosage of prednisone or prednisolone should
be gradually reduced to the lowest dose that prevents signs of hypocortisolism (e.g., lethargy, inappetence).8 Many dogs can be maintained on
relatively small doses of prednisone, supplementing as needed during
times of stress.
8. Q. How often should electrolytes be monitored?
A. During the initial 2 to 3 months of PERCORTEN®-V therapy, electrolytes
should be checked at day 14 and day 25. The following guidelines
should be used for adjusting PERCORTEN-V dosing:
• If all values are normal at day 14 and normal at day 25, change to
30-day frequency
• If all values are normal at day 14 but abnormal at day 25, change to
21-day frequency
• Once stable, check electrolytes every 3 to 4 months
9. Q. What are the necessary steps for transitioning from Florinef ®
(fludrocortisone acetate) to PERCORTEN-V?
A. No weaning is required when switching from Florinef to PERCORTEN-V.
Follow these simple steps simultaneously:
Step 1 – Discontinue all oral salt supplements
Step 2 – Begin PERCORTEN-V injections and discontinue Florinef
Step 3 – Begin daily corticosteroid supplement
(See question 6 for more details on corticosteroid dosing.)
10. Q. How safe is PERCORTEN-V?
A. Through extensive clinical trials lasting nearly 6 years (and including
over 1,000 cases), PERCORTEN-V has demonstrated a wide margin of
safety. Please see back cover for the PERCORTEN-V product insert
and Section 4.3 Clinical review.
It has been demonstrated that PERCORTEN-V is well tolerated with a
low incidence of side effects. In a small percentage of treated dogs,
depression, excessive thirst and urination, digestive, skin and coat
changes, weakness, and injection site reactions (pain, abscesses) may
occur. Some of these effects may resolve with adjustments in dose or
interval of PERCORTEN-V or concomitant glucocorticoid administration.
Do not use in pregnant dogs or in dogs that are suffering from congestive
heart disease, severe renal disease or edema.
11. Q. How quickly does PERCORTEN-V work and when can I expect
my patients to return to normal?
A. The therapeutic effects of PERCORTEN-V is usually observed shortly
after the initial IM dose (often within a few days). For optimal disease
control, and to ensure that your patients are receiving the most appropriate PERCORTEN-V dose, follow the recommended dosing guidelines.
(See questions 2, 6, and 7 for additional dosing information.)
* Florinef is a registered trademark of Bristol-Myers Squibb.
18
7. Client information
sheet
The following two pages may be photocopied and given to your clients when
you prescribe PERCORTEN®-V (desoxycorticosterone pivalate) for their dogs.
This information offers a simple explanation of the basics of Canine Addison’s
Disease and what is required of pet owners whose dogs are in treatment.
19
What dog owners need to know
about Canine Addison’s Disease
Your veterinarian has just prescribed PERCORTEN®-V (desoxycorticosterone pivalate) for your
dog. PERCORTEN-V is the only FDA-approved treatment for Canine Addison’s Disease, and your
veterinarian knows that it’s fast-acting, safe and effective.
Although Canine Addison’s Disease is a serious and potentially fatal condition, with regular injections of PERCORTEN-V and proper medical care, your dog should live a normal, happy life.
Caring for a dog with Canine Addison’s Disease will require frequent visits to your veterinarian
and some extra attention from you. Because this disease is so complex, your veterinarian may
occasionally need to adjust the dosage of PERCORTEN-V as well as the daily supplements you
give your dog. It’s important that you pay careful attention to the veterinarian’s instructions.
Here’s what you need to do:
Medication approximately
every 25 days
Your dog will be receiving a
medication, PERCORTEN-V,
given by your veterinarian
approximately every 25 days.
It is essential to your dog’s
health that this measure be
taken seriously. Make appointments with your veterinarian
and keep them in your calendar.
Your next appointment is on:
________________________
Daily supplements
Watch your dog closely
Your dog needs supplements
of glucocorticoid hormone
replacement. These are given
orally, every day. Over the
next few months, your veterinarian will adjust the daily
dosage. To begin with, follow
these instructions.
It’s important that you note
any symptoms your dog may
have and report them to your
veterinarian on your next visit.
Use this chart to keep track.
Daily dosage: ____________
How to administer:
❏ loss of appetite
❏ depression
❏ diarrhea
❏ frequent urinating
❏ frequent drinking
❏ lethargy
❏ vomiting
❏ weakness
❏ other: ________________
Note: If your dog experiences shock or collapse, call your veterinarian immediately. In scientific studies of PERCORTEN-V, a
small percentage of dogs experienced such symptoms when beginning the treatments, but these symptoms were never fatal.
20
Answering dog owners’ questions
about PERCORTEN -V
®
(desoxycorticosterone pivalate)
1. Q. What is Canine Addison’s Disease?
A. Canine Addison’s Disease is a condition in which a dog’s adrenal glands
aren’t working properly. Adrenal glands produce chemicals called
corticoids, which help regulate the body’s use of food and water.
2. Q. How does PERCORTEN-V work?
A. PERCORTEN-V is a corticoid supplement. It replaces corticoids that your
dog’s adrenal glands aren’t producing.
3. Q. How effective is PERCORTEN-V?
A. PERCORTEN-V is very effective. In fact, one clinical study found
PERCORTEN-V to be 100% effective in treating Canine Addison’s Disease.9
In a separate study, PERCORTEN-V was found to be 96% effective.
4. Q. How soon will PERCORTEN-V start to work?
A. The effects of PERCORTEN-V can usually be seen within 24– 48 hours.
5. Q. Is PERCORTEN-V safe?
A. Yes. Rigorous clinical testing has proven how safe PERCORTEN-V is.
In fact, it’s the only FDA-approved drug for treatment of Canine
Addison’s Disease.
You should speak to your veterinarian about possible side effects. It has been
demonstrated that PERCORTEN-V is well tolerated with a low
incidence of side effects. In a small percentage of treated dogs, depression,
excessive thirst and urination, digestive, skin and coat changes, weakness,
and injection site reactions (pain, abscesses) may occur. Some of these effects
may resolve with adjustments in dose or interval of PERCORTEN-V or concomitant glucocorticoid administration. Do not use in pregnant dogs or in dogs
that are suffering from congestive heart disease, severe renal disease or edema.
Please see brief summary at bottom of page for more information.
6. Q. Is PERCORTEN-V recommended for pregnant dogs?
A. Pregnant dogs should not be treated with PERCORTEN-V.
7. Q. Will my dog have Addison’s Disease for the rest of its life?
A. Yes, but with proper medical management, your dog may live a normal life
span compared to dogs without Addison’s Disease.
Brief Summary: Please consult full package insert for more information. Indications: PERCORTEN-V (desoxycorticosterone pivalate) Injectable Suspension is indicated as replacement
therapy for the mineralocorticoid deficit in dogs with primary adrenocortical insufficiency. Warnings: Do not use this drug in pregnant dogs. Do not use in dogs suffering from congestive
heart disease, severe renal disease or edema. Precautions: Some patients may exhibit side effects if dosage is too high or prolonged. Some of these effects may resolve with adjustments in
dose or intervals of PERCORTEN-V of concomitant glucocorticoid medication. Adverse Reactions: The following adverse reactions have been reported following the use of PERCORTEN-V:
depression, polyuria, polydipsia, anorexia, skin and coat changes, diarrhea, vomiting, weakness, weight loss, incontinence, pain on injection and injection site abscess. Caution: U.S. Federal
law restricts this drug to use by or on the order of a licensed veterinarian. How Supplied: PERCORTEN-V is available in 4 ml multiple-dose vials and packed one vial per carton, each ml
contains 25 mg desoxycorticosterone pivalate. Storage Conditions: PERCORTEN-V should be stored at room temperature between 59° F and 86° F (15°-30° C).
(NADA 141-029, Approved by the FDA)
© 2005 Novartis Animal Health, US, Inc.
PERCORTEN-V is a registered trademark of Novartis AG.
8. References
1. Hardy RM: Hypoadrenal gland disease. In Ettinger SJ, Feldman EC, editors.
Textbook of Veterinary Internal Medicine. Philadelphia: WB Saunders; 1995.
p 1579–1593.
2. Grooters AM. Addison’s Disease: Diagnosis and Treatment. In: North
American Veterinary Conference 1998 Proceedings. Gainesville, FL: Eastern
States Veterinary Association; 1998. p 238–242.
3. Kelch WJ. Canine hypoadrenocorticism (Addison’s Disease). The Compendium,
June 1998.
4. Tilley LP, Smith FWK: Hypoadrenocorticism (Addison’s Disease). In Tilley
LP, Smith FWK, editors. The 5-minute Veterinary Consult. Philadelphia:
Williams & Wilkins, 1997. p 716–717.
5. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory
findings in dogs with hypoadrenocorticism: 225 cases (1979–1993). Journal of
the American Veterinary Medical Association 1996; 208: p 85–91.
6. Chow E, Lynn R, Pavkov K, et al. Tolerability of desoxycorticosterone pivalate
in dogs with normal adrenal function. In 9th Annual Veterinary Medicine
Forum. Journal of Veterinary Internal Medicine. American College of
Veterinary Internal Medicine; 1991. Abstract.
7. Feldman EC, Lynn R. Treatment of canine hypoadrenocorticism with desoxycorticosterone pivalate. British Veterinary Journal 1991; 147: p 478– 483.
8. Nelson R and Couto C et al. Essentials of Small Animal Internal Medicine.
Mosby Yearbook: 1992. p 600 – 605.
9. Freedom of Information Summary. Novartis Animal Health US, Inc., 1997.
10. Feldman EC and Nelson RW. Canine and Feline Endrocrinology and
Reproduction, Third Edition. Philadelphia: WB Saunders; 1996. p 296-431.
PERCORTEN -V is a registered trademark of Novartis AG.
22
show signs of hypernatremia or hypokalemia. The dosage of
PERCORTEN-V should be reduced in these patients.
3-454-936
NAH/PER/V1/3
07/02
CAUTION:
Federal (U.S.A.) law restricts this drug to use by or on the order of a
licensed veterinarian.
DESCRIPTION:
The active ingredient in PERCORTEN-V is desoxycorticosterone
pivalate (DOCP). It is a mineralocorticoid hormone and an analog of
desoxycorticosterone. It is white, odorless, and stable in air. It is
practically insoluble in water, sparingly soluble in acetone, slightly
soluble in methanol, ether and vegetable oils. The molecular weight is
414.58. It is designated chemically as 21 (2,2-dimethyl-1-oxopropoxy)pregn-4-ene-3,20-dione. The empirical formula is C26H38O4 and the
structural formula is:
PERCORTEN -V is a white aqueous suspension. Each ml contains 25
mg of desoxycorticosterone pivalate. Inactive ingredients are water for
injection, methylcellulose, sodium carboxymethylcellulose, polysorbate
80, sodium chloride, and thimerosal.
CLINICAL PHARMACOLOGY:
Desoxycorticosterone pivalate (DOCP), like other adrenocorticoid
hormones, is thought to act by controlling the rate of synthesis of
proteins. It reacts with receptor proteins in the cytoplasm to form a
steroid-receptor complex. This complex moves into the nucleus where
it binds to chromatin that results in genetic transcription of cellular
DNA to messenger RNA. The steroid hormones appear to induce
transcription and synthesis of specific proteins which produce the
physiologic effects seen after administration.
DOCP is a long-acting ester of desoxycorticosterone acetate (DOCA)
which is recognized as having the same qualitative effects as the
natural mineralocorticoid hormone aldosterone.
The most important effect of DOCP is to increase the rate of renal
tubular absorption of sodium. This effect is seen most intensely in the
thick portion of the ascending limb of the loop of Henle. It also increases
sodium absorption in the proximal convoluted tubule but this effect
is less important in sodium retention. Chloride follows the sodium out
of the renal tubule.
Another important effect of DOCP is enhanced renal excretion of
potassium. This effect is driven by the resorption of sodium that pulls
potassium from the extracellular fluid into the renal tubules, thus
promoting potassium excretion.
DOCP also acts to increase extracellular fluid volume. The enhanced
retention of sodium, chloride and bicarbonate creates an osmotic
gradient that promotes water absorption from the renal tubules. The
extracellular fluid volume is supported. This expands the blood volume
and improves the venous return to the heart and cardiac output. The
expanded blood volume and increased cardiac output may result in
elevated blood pressure. PERCORTEN-V prevents the life threatening
hypotensive shock and pre-renal azotemia observed in animals suffering
from hypoadrenocorticism.
The effects of PERCORTEN-V on electrolytes and extracellular fluid
volume are dependent on a functioning kidney. Animals suffering
from hypovolemia, pre-renal azotemia, and inadequate tissue perfusion
must be rehydrated with intravenous fluid (saline) therapy before
starting PERCORTEN-V therapy. Primary renal disease should be
ruled out before starting PERCORTEN-V therapy.
DOCP is an insoluble ester of desoxycorticosterone. The crystals are
injected intramuscularly as a microcrystalline depot where they slowly
dissolve over time.
INDICATION:
For use as replacement therapy for the mineralocorticoid deficit in
dogs with primary adrenocortical insufficiency.
WARNING:
Do not use this drug in pregnant dogs. Do not use in dogs suffering
from congestive heart disease, severe renal disease or edema.
Keep this and all drugs out of the reach of children. In case of human
consumption, contact a physician or Poison Control Center immediately.
PRECAUTIONS:
Some patients are more sensitive to the actions of PERCORTEN-V and
may exhibit side effects in an exaggerated degree. Some patients may
Like other adrenocortical hormones, PERCORTEN-V may cause severe
side effects if dosage is too high or prolonged. It may cause polyuria,
polydipsia, increased blood volume, edema and cardiac enlargement.
Excessive weight gain may indicate fluid retention secondary to sodium
retention. PERCORTEN-V should be used with caution in patients with
congestive heart disease, edema or renal disease.
ADVERSE REACTIONS:
The following adverse reactions have been reported following the use
of PERCORTEN-V: depression, polyuria, polydipsia, anorexia, skin and
coat changes, diarrhea, vomiting, weakness, weight loss, incontinence,
pain on injection and injection site abscess. Some of these effects
may resolve with adjustments in dose or interval of PERCORTEN-V or
concomitant glucocorticoid medication.
EFFICACY:
PERCORTEN-V given intramuscularly at the appropriate dose and
interval is effective in replacing the mineralocorticoid deficit in dogs
suffering from primary hypoadrenocorticism.
Results of two 75-day clinical studies in dogs with primary
hypoadrenocorticism have demonstrated the clinical efficacy of
PERCORTEN-V. Each dog received three doses of PERCORTEN-V (on
days 0, 25 and 50). The results are summarized below.
Clinical Study Number
01
Number of Dogs
49
Average Diagnostic Values:
Serum Sodium (mEq/L)
128.40
Serum Potassium (mEq/L)
7.28
Sodium/Potassium Ratio
18.09
ACTH Stimulation Test:
Cortisol Resting (µg/dI)
0.28
Cortisol Post
Stimulation (µg/dI)
0.27
Average PERCORTEN-V Dose (mg/lb):
Day 0
0.97
Day 25
0.96
Day 50
0.94
Concomitant
Glucocorticoid (Pred)
47%
Sodium/Potassium Ratios
Day 0
25.18
36.36
Day 14
Day 25
29.64
34.94
Day 39
Day 50
30.33
35.30
Day 64
Day 75
30.32
96%
% Efficacy Therapy
02
18
130.72
7.47
17.86
0.68
1.34
0.99
0.99
0.97
Dosage:1,2
In treating canine hypoadrenocorticism, PERCORTEN-V replaces the
mineralocorticoid hormones only. Glucocorticoid replacement must be
supplied by small daily doses of glucocorticoid hormones (e.g., prednisone
or prednisolone) (0.2– 0.4 mg/kg/day).
Dosage requirements are variable and must be individualized on the
basis of the response of the patient to therapy. Begin treatment with
PERCORTEN-V at a dose of 1.0 mg per pound of body weight every
25 days. In some patients the dose may be reduced. Serum sodium
and potassium levels should be monitored to assure the animal is
properly compensated. Most patients are well controlled with a dose
range of 0.75 to 1.0 mg per pound of body weight, given every 21 to
30 days.
The well-controlled patient will have normal electrolytes at 14 days
after administration or may exhibit slight hyponatremia and hyperkalemia.
This needs no additional therapy as long as the patient is active and
eating normally. Watch closely for depression, lethargy, vomiting or
diarrhea which indicate a probable glucocorticoid deficiency.
At the end of the 25-day dosing interval, the patient should be clinically normal and have normal serum electrolytes. Alternatively, they may
have slight hyponatremia and slight hyperkalemia. This constellation of
signs indicate that the dosage and dosage interval should not be altered.
If the dog is not clinically normal or serum electrolytes are abnormal,
then the dosage interval should be decreased 2–3 days.
Occasionally, dogs on PERCORTEN-V therapy may develop polyuria
and polydipsia (PU/PD). This usually indicates excess glucocorticoid,
but may also indicate PERCORTEN-V excess. It is prudent to begin by
decreasing the glucocorticoid dose first. If the PU/PD persists, then
decrease the dose of PERCORTEN-V without changing the interval
between doses.
Please note: Failure to administer glucocorticoids is the most common
reason for treatment failure. Signs of glucocorticoid deficiency include:
depression, lethargy, vomiting and diarrhea. Such signs should be
treated with high doses of injectable glucocorticoids (prednisolone or
dexamethasone), followed by continued oral therapy (0.2 – 0.4 mg/kg/
day). Oral supplementation with salt (NaCI) is not necessary with animals
receiving PERCORTEN-V.
Guide to Maintenance Therapy
39%
26.42
30.59
100%
Case Management: 1,2
An accurate diagnosis of primary canine adrenocortical insufficiency
is of paramount importance for treatment success and should be
established before initiation of PERCORTEN-V therapy. While
hyponatremia and hyperkalemia are highly suggestive of adrenocortical
insufficiency, they are not pathognomonic. A definitive diagnosis can
only be made with an ACTH stimulation test. At diagnosis, classic
cases of canine adrenocortical insufficiency may include clinical signs.
Those signs are anorexia, lethargy, depression, weakness, vomiting
and/or regurgitation, weight loss, diarrhea and collapse, serum sodium
values less than 135 mEq/L, serum potassium greater than 6 mEq/L,
sodium/potassium ratios below 25:1, plasma or serum cortisol concentration less than 4 µg/dl pre-and- post ACTH administration.
Once the diagnosis is made, immediate therapy must be given to
normalize electrolyte imbalance, correct hypovolemic shock and reestablish normal homeostasis. Such therapy should include, large
volumes of intravenous physiologic saline, glucocorticoids (i.e.,
prednisolone, dexamethasone) at shock doses and PERCORTEN-V.
Once the acute crisis has passed, renal and cardiovascular function
should return to normal. Then begin chronic lifelong therapy with
PERCORTEN-V and glucocorticoids.
SAFETY: 3
In a laboratory study the safety of PERCORTEN-V was established in
five month old Beagle dogs. PERCORTEN-V was administered IM to 24
Beagles at 0, 2.2, 6.6 or 11 mg/kg of body weight daily over a consecutive 3-day period every 28 days (equivalent to a cumulative monthly
dosage of 0,6.6,19.8 or 33 mg/kg) for 6 months. This resulted in no
mortality or any significant effects on body weight, food consumption,
and ophthalmic observations at any dose level. However, polyuria and
polydipsia were noted and creatinine concentration decreased (14-89
mg/dl) in the 1X, 3X and 5X groups. Histopathological changes
were only observed in the kidneys when PERCORTEN-V was administered at ≥ 6.6 mg/kg. The primary renal lesion consisted of
glomerulonephropathy seen in all males at ≥ 6.6 mg/kg, in one female
at 6.6 mg/kg, and in all females at 11 mg/kg. Other possible treatmentrelated lesions in the kidney, observed sporadically in the 6.6 and 11.0
mg/kg groups, were tubular hyperplasia, inflammation and tubular
dilatation. Glomerulonephropathy may possibly be attributed to the
pharmacological effects of the drug although there were no clinical
measurements assessed in this study. In conclusion, PERCORTEN-V
was well tolerated, when administered at 2.2 mg/kg on three consecutive days in every 28-day period for six months.
Customer Service: 1-800-332-2761
Professional Services: 1-800-637-0281
www.petwellness.com
Starting Dose:
DOCP 1 mg/lb every 25 days
Prednisone 0.2 – 0.4 mg/kg/day
Guides for Adjustment:
Clinical Problem/Solution
Polyuria/Polydipsia
• decrease prednisone dose first,
• then decrease DOCP dose,
• do not change DOCP interval
Depression, lethargy, vomiting or diarrhea
• increase prednisone dose
Hyperkalemia, Hyponatremia
• decrease DOCP interval 2–3 days
ADMINISTRATION:
Before injection, shake the vial thoroughly to mix the microcrystals
with the suspension vehicle. PERCORTEN-V suspension is to be injected
intramuscularly. Care should be used to prevent inadvertent intravenous injection, which may cause acute collapse and shock. Such
animals should receive immediate therapy for shock with intravenous
fluids and glucocorticoids.
HOW SUPPLIED:
Multiple-Dose Vials, 4 ml, each ml containing 25 mg desoxycorticosterone
pivalate (DOCP), 10.5 mg methylcellulose, 3 mg sodium
carboxymethylcellulose, 1 mg polysorbate 80, and 8 mg sodium chloride
with 0.002% thimerosal added as preservative in water for injection.
Packed one vial per carton.
STORAGE:
Store at room temperature, preferably between 15° and 30°C (59° and
86°F). Protect from light. Protect from freezing.
References:
1. Canine and Feline Endocrinology and Reproduction. Second Edition,
E. C. Feldman and R. W. Nelson, W. B. Saunders Co., New York, 1996.
2. Textbook of Veterinary Internal Medicine. Fourth Edition, S. J. Ettinger
and E. C. Feldman editors, W. B. Saunders, Co., New York, 1995.
3. Toxicity of desoxycorticosterone pivalate given at high doses to clinically
normal Beagles for six months, E. Chow, W. R. Campbell, J. C. Turnier,
R. C. Lynn and K. L. Pavkov, Am. J. Vet. Res. 54(11):1954–1961, 1993.
Manufactured for:
Novartis Animal Health US, Inc.
Greensboro, NC 27408-6402, USA
NADA No.141-029, Approved by FDA.
©2004
Novartis Animal Health US, Inc.
NAH/PER/VI/3
07/02
PERCORTEN-V is a registered trademark of Novartis AG.
PER980002B